Previous studies have shown that an imbalance in autonomic efferent neuronal tone, with reduced parasympathetic activity coupled with increased and heterogeneous sympathetic outflow, increases the risk of cardiac arrhythmias and sudden death. While the progression of cardiac disease affects multiple aspects of cardiac control, it is those changes in peripheral autonomic neuronal processing and their projections that ultimately determine the neuronal coordination of the heart. The intrinsic cardiac nervous system (ICN), the final common pathway for such neural control, integrates information from multiple inputs and mediates short- loop reflex control of regional cardiac indices. Although multiple studies have focused on cardiac stress- induced changes in post-ganglionic innervation patterns to the heart, little attention has been paid to the critical role of information processing within autonomic ganglia and how they remodel/adapt to imposed stress. It is our hypothesis that cardiac stress-induced adaptations within the ICN facilitate coordination of efferent parasympathetic output and that these changes are reflected in functional and phenotypic alterations in select intrinsic cardiac neuronal populations. These cardioprotective adaptations within the ICN could counteract, in part, the maladaptive effects of excessive sympatho-excitation associated cardiac stress. Numerous studies have identified molecular mechanisms associated with cardiac remodeling, including increased activity of the renin-angiotensin system, changes in nitric oxide (NO) production, and alterations in end-organ sensitivity to neurotransmitters. For each of these factors, while their direct effects on myocyte function are well established, recent data indicates that many of their cardiac effects are mediated via alterations in function within the cardiac nervous system. To specifically address these points this proposal will evaluate how the elements of the ICN adapt to chronic disease using two different animal models of heart disease: myocardial infarction (MI) and chronic pressure overload (PO). The proposed experiments will focus on two specific adaptations of the ICN: (1) changes in neuronal responses to neuromodulators and (2) changes in ICN network efficiency. We will also evaluate the efficacy of targeted pharmacologic therapy to mitigate adverse remodeling of the ICN. Using a whole mount preparation of the guinea pig cardiac plexus, we will evaluate the physiological responses of individual intrinsic cardiac neurons to autonomic neurotransmitters with and without potential neuromodulators, such as angiotensin II and NO in tissues from control, MI and PO animals to characterize stress-induced changes in neuronal responses. In addition, we will evaluate the output of individual neurons to stimulation of vagal and intraganglionic fiber inputs to evaluate integrated network function. Changes in neuronal activity will then be compared between untreated disease models and disease models treated with standard therapeutics such as 2-receptor blockage, AT receptor inhibition, or inhibition of NO generation, to determine if these therapies modulate the ICN function.